CASP6

Summary

CASP6 (caspase 6, HGNC:1507) is a protein-coding gene on chromosome 4q25, encoding Caspase-6 (P55212). Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity.

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms.

Source: NCBI Gene 839 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 59 total
• GTEx eGene: eQTL in 31 tissues, sQTL in 3 (q < 0.05)
• ChEMBL bioactivity: 10 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.95 (unconstrained)
• MANE Select transcript: NM_001226
• Notable: 59 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1507
Approved symbol	CASP6
Name	caspase 6
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	MCH2, caspase-6, CSP-6
Ensembl gene	ENSG00000138794
Ensembl biotype	protein_coding
OMIM	601532
Entrez	839

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000265164

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 4, TSL 3: 1

ENST00000265164, ENST00000352981, ENST00000503684, ENST00000505117, ENST00000505486, ENST00000507550, ENST00000508203, ENST00000510324, ENST00001022051, ENST00001059029, ENST00001129774, ENST00001138264

RefSeq mRNA: 2 — MANE Select: NM_001226 NM_001226, NM_032992

CCDS: CCDS3684, CCDS3685

Canonical transcript exons

ENST00000265164 — 7 exons

Exon	Start	End
ENSE00000935047	109697622	109697768
ENSE00001018825	109703356	109703445
ENSE00001820381	109688628	109689568
ENSE00003504478	109690850	109691009
ENSE00003513525	109698300	109698342
ENSE00003596076	109696410	109696486
ENSE00003650192	109694525	109694700

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 96.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5693 / max 71.5713, expressed in 1678 samples.

Highest expression (Bgee): rectum, mucosa of transverse colon, oocyte, secondary oocyte, jejunal mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CASP6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 31 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	2.9e-20	+0.45	4:109728735:G:T
Heart Atrial Appendage	eqtl	1.7e-18	+0.41	4:109698378:T:G
Brain Cerebellum	eqtl	1.3e-13	+0.46	4:109728735:G:T
Cells Cultured fibroblasts	eqtl	4.4e-10	+0.67	4:109696125:C:A
Artery Tibial	eqtl	3.4e-08	+0.73	4:109696125:C:A
Brain Nucleus accumbens basal ganglia	eqtl	8.4e-08	+0.34	4:109731578:A:C
Brain Caudate basal ganglia	eqtl	1.6e-07	+0.32	4:109698378:T:G
Pituitary	eqtl	5.8e-07	+0.31	4:109728735:G:T
Artery Aorta	eqtl	1.4e-06	+0.90	4:109696125:C:A
Brain Frontal Cortex BA9	eqtl	1.5e-05	-0.28	4:109737700:C:G
Brain Cortex	eqtl	2.7e-05	-0.26	4:109737700:C:G
Skin Not Sun Exposed Suprapubic	eqtl	4.4e-05	+0.68	4:109696493:G:A
Adipose Subcutaneous	eqtl	1.1e-04	+0.69	4:109698708:A:AAC
Colon Sigmoid	eqtl	1.2e-04	+0.73	4:110113444:G:A
Skin Sun Exposed Lower leg	eqtl	2.9e-04	-0.15	4:109660944:T:C
Brain Hypothalamus	eqtl	4.0e-04	-0.33	4:109737700:C:G
Heart Left Ventricle	eqtl	4.6e-04	+0.27	4:109728735:G:T
Stomach	eqtl	5.9e-04	+0.45	4:109698708:A:AAC
Esophagus Mucosa	eqtl	8.3e-04	+0.41	4:110002635:G:C
Brain Putamen basal ganglia	eqtl	1.2e-03	+0.32	4:109728735:G:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
53600	6.5693	1678

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	96.27	gold quality
mucosa of transverse colon	UBERON:0004991	95.57	gold quality
oocyte	CL:0000023	95.50	gold quality
secondary oocyte	CL:0000655	94.72	gold quality
jejunal mucosa	UBERON:0000399	94.65	gold quality
duodenum	UBERON:0002114	92.59	gold quality
pancreatic ductal cell	CL:0002079	92.56	gold quality
colonic mucosa	UBERON:0000317	92.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.64	gold quality
buccal mucosa cell	CL:0002336	91.46	gold quality
transverse colon	UBERON:0001157	91.10	gold quality
islet of Langerhans	UBERON:0000006	89.16	gold quality
amniotic fluid	UBERON:0000173	89.02	gold quality
intestine	UBERON:0000160	88.65	gold quality
large intestine	UBERON:0000059	88.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.59	gold quality
ventricular zone	UBERON:0003053	88.58	gold quality
small intestine	UBERON:0002108	88.47	gold quality
colon	UBERON:0001155	88.45	gold quality
body of pancreas	UBERON:0001150	87.80	gold quality
colonic epithelium	UBERON:0000397	87.77	gold quality
cervix squamous epithelium	UBERON:0006922	87.72	silver quality
pancreas	UBERON:0001264	87.65	gold quality
right lobe of liver	UBERON:0001114	87.29	gold quality
ileal mucosa	UBERON:0000331	86.97	gold quality
palpebral conjunctiva	UBERON:0001812	86.83	gold quality
gall bladder	UBERON:0002110	86.34	gold quality
ganglionic eminence	UBERON:0004023	86.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.23	gold quality
germinal epithelium of ovary	UBERON:0001304	86.17	gold quality
monocyte	CL:0000576	85.85	gold quality
endometrium	UBERON:0001295	85.39	gold quality
mononuclear cell	CL:0000842	85.34	gold quality
leukocyte	CL:0000738	85.20	gold quality
sigmoid colon	UBERON:0001159	85.20	gold quality
body of stomach	UBERON:0001161	85.20	gold quality
stromal cell of endometrium	CL:0002255	84.73	gold quality
metanephros cortex	UBERON:0010533	84.49	gold quality
stomach	UBERON:0000945	84.22	gold quality
visceral pleura	UBERON:0002401	83.81	gold quality
liver	UBERON:0002107	83.72	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.54	gold quality
right adrenal gland	UBERON:0001233	83.46	gold quality
urinary bladder	UBERON:0001255	83.42	gold quality
right ovary	UBERON:0002118	83.30	gold quality
embryo	UBERON:0000922	83.22	gold quality
right adrenal gland cortex	UBERON:0035827	83.07	gold quality
vermiform appendix	UBERON:0001154	82.96	gold quality
jejunum	UBERON:0002115	82.95	gold quality
minor salivary gland	UBERON:0001830	82.72	gold quality
left ovary	UBERON:0002119	82.61	gold quality
ovary	UBERON:0000992	82.47	gold quality
parietal pleura	UBERON:0002400	82.44	gold quality
calcaneal tendon	UBERON:0003701	82.36	gold quality
lymph node	UBERON:0000029	82.25	gold quality
mucosa of urinary bladder	UBERON:0001259	82.25	silver quality
pleura	UBERON:0000977	82.03	gold quality
mouth mucosa	UBERON:0003729	82.03	gold quality
seminal vesicle	UBERON:0000998	81.87	gold quality
right lobe of thyroid gland	UBERON:0001119	81.83	gold quality
right uterine tube	UBERON:0001302	81.77	gold quality
skin of hip	UBERON:0001554	81.77	gold quality
granulocyte	CL:0000094	81.73	gold quality
lower esophagus	UBERON:0013473	81.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.69	gold quality
epithelium of mammary gland	UBERON:0003244	81.68	gold quality
smooth muscle tissue	UBERON:0001135	81.65	gold quality
descending thoracic aorta	UBERON:0002345	81.63	gold quality
adult mammalian kidney	UBERON:0000082	81.60	gold quality
endocervix	UBERON:0000458	81.59	gold quality
left adrenal gland	UBERON:0001234	81.53	gold quality
skin of abdomen	UBERON:0001416	81.49	gold quality
uterus	UBERON:0000995	81.46	gold quality
esophagus	UBERON:0001043	81.39	gold quality
caecum	UBERON:0001153	81.38	gold quality
mammary duct	UBERON:0001765	81.34	gold quality
corpus epididymis	UBERON:0004359	81.33	gold quality
left lobe of thyroid gland	UBERON:0001120	81.27	gold quality
fundus of stomach	UBERON:0001160	81.26	gold quality
apex of heart	UBERON:0002098	81.25	gold quality
squamous epithelium	UBERON:0006914	81.20	gold quality
popliteal artery	UBERON:0002250	81.14	gold quality
esophagus mucosa	UBERON:0002469	81.13	gold quality
tibial artery	UBERON:0007610	81.13	gold quality
thyroid gland	UBERON:0002046	81.04	gold quality
aorta	UBERON:0000947	81.00	gold quality
esophagus squamous epithelium	UBERON:0006920	80.98	gold quality
lower lobe of lung	UBERON:0008949	80.96	gold quality
thoracic aorta	UBERON:0001515	80.95	gold quality
left adrenal gland cortex	UBERON:0035825	80.93	gold quality
skin of leg	UBERON:0001511	80.92	gold quality
ascending aorta	UBERON:0001496	80.78	gold quality
spleen	UBERON:0002106	80.77	gold quality
mucosa of stomach	UBERON:0001199	80.71	gold quality
mammary gland	UBERON:0001911	80.70	gold quality
body of uterus	UBERON:0009853	80.70	gold quality
saliva-secreting gland	UBERON:0001044	80.67	gold quality
zone of skin	UBERON:0000014	80.66	gold quality
thoracic mammary gland	UBERON:0005200	80.66	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.20
E-GEOD-110499	no	256.07

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Duodenum	tissue	38.1	medium
Small intestine	tissue	34.5	high
Colon	tissue	32.9	high
Rectum	tissue	29.5	high
Liver	tissue	15.3	not detected
Stomach 1	tissue	14.8	high
Pancreas	tissue	10.8	low
Thymus	tissue	10.7
Ovary	tissue	10.2	medium
Skin 1	tissue	10.1	low
Bone marrow	tissue	10.1	low
Breast	tissue	9.8	medium
Kidney	tissue	9.8	high
Lymph node	tissue	9.0	low
Gallbladder	tissue	8.6	medium
Hypothalamus	tissue	8.5
Prostate	tissue	8.5	low
Cerebellum	tissue	8.3	not detected
Salivary gland	tissue	8.1	low
Medulla oblongata	tissue	8.0
Superior colliculi	tissue	8.0
Substantia nigra	tissue	7.9
Thyroid gland	tissue	7.9	not detected
Spinal cord	tissue	7.9
Septum	tissue	7.9
Appendix	tissue	7.9	high
Periaqueductal gray	tissue	7.8
Amygdala	tissue	7.7
Olfactory bulb	tissue	7.7
Urinary bladder	tissue	7.6	high
Midbrain	tissue	7.6
Lung	tissue	7.3	not detected
Endometrium 1	tissue	7.2	medium
Cervix	tissue	7.1	medium
Tonsil	tissue	7.1	low
Fallopian tube	tissue	7.1	low
Hippocampal formation	tissue	6.9
Entorhinal cortex	tissue	6.9
Smooth muscle	tissue	6.8	not detected
Spleen	tissue	6.8	not detected
Pons	tissue	6.7
Corpus callosum	tissue	6.4
Cerebral cortex	tissue	6.2	not detected
Retrosplenial cortex	tissue	6.2
Temporal cortex	tissue	6.2
Seminal vesicle	tissue	6.1	low
Insular cortex	tissue	6.1
Choroid plexus	tissue	5.9
Thalamus	tissue	5.9
Ventral forebrain	tissue	5.8
Vagina	tissue	5.6	not detected
Adipose tissue	tissue	5.6	not detected
Basal ganglia	tissue	5.5	not detected
Occipital cortex	tissue	5.5
Hippocampus	tissue	5.4	not detected
Putamen	tissue	5.3
Heart muscle	tissue	5.0	not detected
Retrosplenial and cingulate cortex	tissue	5.0
Prefrontal cortex	tissue	4.9
Somatosensory cortex	tissue	4.9

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal spinal cord (7.9), Ventral spinal cord (7.6), Subiculum (6.8), Anterior insular cortex, dorsal (6.6), White matter (6.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, MAF, TP53

miRNA regulators (miRDB)

Targeting CASP6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 40 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-5089-5P	98.45	66.06	1388

Functional genomics

gnomAD constraint: pLI 7.97e-05, LOEUF 0.953, missense Z 0.755 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000265164 — one region, missense o/e 0.91.

Literature-anchored findings (GeneRIF, showing 40)

• identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. (PMID:12089322)
• Pro-CASP6 was the only proenzyme whose localization was limited to the cytosol in U937 cells during TPA-induced differentiation. (PMID:12145703)
• ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system. (PMID:15273717)
• induced and utilized by human Astrovirus Yuc8 to promote processing of the capsid precursor and dissemination of the viral particles in CAC0-2 cells. (PMID:15280469)
• programmed cell death was executed by caspase 6 in Streptococcus pneumoniae infected lung epithelium (PMID:15321985)
• CASP-6 cleaves the N terminus of tau in vitro at D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. This suggests a role for caspase-6 & N-terminal truncation of tau during neurofibrillary tangle & Alzheimer’s disease progression. (PMID:15356202)
• caspase-2, -6 and -7 expression in gastric cancer cells is decreased compared to in normal gastric mucosal cells (PMID:15511269)
• caspase 6 cleaves periplakin at an unconventional recognition site, amino acid sequence TVAD (PMID:15654952)
• results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons; also results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death (PMID:16123779)
• results suggest that splitting of BL41-E95-A cells induces de novo synthesis of a protein involved in the activation of casp-6 and casp-8, which cleaves 5-LO. (PMID:16135563)
• caspase-6 and its cleavage of lamin A are critical in apoptotic signaling triggered by resveratrol in the colon carcinoma cells, which can be activated in the absence of Bax or p53 (PMID:16518869)
• data indicate that the CASP6 gene is occasionally mutated in gastric and colorectal carcinomas; also, the data suggest the possibility that deficiency of caspase-6 expression might contribute to the pathogenesis of gastric cancers (PMID:16948818)
• Caspase-6 was overexpressed in 52.9% of the 210 cases studied, showing predominantly cyoplasmic with some nuclear staining. (PMID:16977583)
• Active caspase-6 could be an early instigator of neuronal dysfunction. (PMID:17392160)
• The experiments revealed that N induces the intrinsic apoptotic pathway, resulting in processing of N at residues 400 and 403 by caspase-6 and/or caspase-3. (PMID:18155731)
• Resveratrol displays converse dose-related effects on fluorouracil-evoked colon cancer cell apoptosis: the role of CASP6 is reported. (PMID:18497562)
• Expression of caspase 6 and caspase 14 genes were different between normal skin of keloid-prone individuals and normal skin of keloid-resistant patients. (PMID:18762957)
• Caspase 6 cleaves cyclin B1 during mitotic catastrophe. Mitotic & apoptotic functions may be linked by caspase-dependent processing of mitotic activators. (PMID:18820706)
• Report co-localization of hyperphosphorylated tau and caspases 3/6 in the brainstem of Alzheimer’s disease patients. (PMID:18946722)
• During hypoxia in tube-forming endothelial cells, caspase-7 is responsible for chromatin condensation and nuclear fragmentation while caspase-6 is responsible for DNA ladder formation. (PMID:19022247)
• The crystal structure of caspase-6, a selective effector of axonal degeneration. (PMID:19694615)
• p53 activation enhances XIAP inhibition-induced cell death by promoting mitochondrial release of second mitochondria-derived activator of caspases (SMAC) and by inducing the expression of caspase-6. (PMID:19897582)
• Casp-6 is activated in familial forms of Alzheimer disease, as previously observed in sporadic forms. (PMID:19915487)
• results show that p97 is cleaved by Casp6 in Alzheimer’s disease and suggest p97 cleavage as an important mechanism for ubiquitin proteasome system impairment (PMID:20427671)
• Data showed that prostate cancer and PIN cells display higher expression of the proapoptotic proteins caspase-6 and BNIP3 than normal cells. (PMID:20437871)
• The NPM mutant specifically inhibits the activities of the cell-death proteases, caspase-6 and -8, through direct interaction with their cleaved, active forms, but not the immature procaspases. (PMID:20606168)
• These results imply that pro-Casp6b could negatively regulate pro-Casp6a activation in neurons and prevent Casp6a-mediated axonal degeneration. (PMID:20682790)
• a central and so far underappreciated role of caspase-8 dimerization/dissociation in avoiding unwanted cell death by lethal amplification of caspase responses via the caspase-8, -3, -6 loop. (PMID:20702410)
• CASP6 can be activated and regulated through intramolecular self-cleavage. (PMID:20890311)
• Intact IRAK-M is strongly expressed in resting alveolar macrophages but is cleaved in patients with pneumonia via neutrophil-mediated induction of CASP-6 activity. (PMID:21098228)
• These data suggest that caspase-6 undergoes a significant conformational change upon substrate binding, adopting a structure that is more like canonical caspases. (PMID:21111746)
• Data suggest that Casp4, Casp 6 and TNFSF10 are differentially expressed in potentially fertile and subfertile men and represent useful biomarkers for predicting male fertility in combination with P1 and P2. (PMID:21317160)
• New crystal form of apo-caspase-6 is presented in canonical conformation by identifying the previous apostructure as a hydrogen-ion concentration (pH)-inactivated form of caspase-6. (PMID:21621544)
• Caspase-6 cleaves human TERT at residues E129 and D637 as part of the apoptosis pathway in cultured cells. (PMID:21936563)
• Results showed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design. (PMID:22433863)
• peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization (PMID:22683611)
• Results demonstrate that in the absence of caspase 6 activity, intrinsic triggers of apoptosis induce the receptor-interacting-kinase-1-dependent production of pro-inflammatory cytokines. (PMID:22858542)
• binding of zinc at the exosite is the primary route of inhibition, potentially locking caspase-6 into the inactive helical conformation. (PMID:22891250)
• Caspase 6 activity in entorhinal cortex identifies aged individuals at risk for developing Alzheimer’s disease. (PMID:23402898)
• Significant associations have been found between CpG sites and patient sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. (PMID:24058506)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp6b.1	ENSDARG00000025608
danio_rerio	casp6b.2	ENSDARG00000070368
danio_rerio	casp6a	ENSDARG00000093405
mus_musculus	Casp6	ENSMUSG00000027997
rattus_norvegicus	Casp6	ENSRNOG00000052613
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1312921) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cerebral cortex morphology	1
decreased locomotor activity	1
abnormal response to novel object	1
abnormal neuron physiology	1
abnormal lens development	1
decreased susceptibility to neuronal excitotoxicity	1
increased striatum size	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q5IS54	99.6%	Diamond
Macaca fascicularis	Q2PFV2	96.0%	Diamond
Saimiri boliviensis boliviensis	Q5IS99	96.0%	Diamond
Mesocricetus auratus	Q60431	92.1%	Diamond
Oryctolagus cuniculus	Q8MJC3	90.6%	Diamond
Felis catus	Q8MJU1	89.9%	Diamond
Canis lupus familiaris	Q8MKI5	89.9%	Diamond
Sus scrofa	Q95ND5	88.8%	Diamond
Bos taurus	Q3T0P5	88.3%	Diamond
Caenorhabditis remanei	P45436	84.5%	Diamond
Gallus gallus	F1NV61	73.9%	Diamond
Spodoptera frugiperda	P89116	66.7%	Diamond
Xenopus laevis	P55866	59.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SEC24B	protein-coding	10427
MCUB-AS1	ncRNA	124900755
MCUB	protein-coding	55013
MIR576	ncRNA	693161
CFI	protein-coding	3426
PLA2G12A	protein-coding	81579
GAR1-DT	ncRNA	124900758

Protein

Protein identifiers

Caspase-6 — P55212 (reviewed: P55212)

Alternative names: Apoptotic protease Mch-2

All UniProt accessions (3): D6RBM3, D6RHU3, P55212

UniProt curated annotations — full annotation on UniProt →

Function. Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity. Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation. Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution. Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis. Cleaves PARK7/DJ-1 in cells undergoing apoptosis. Involved in intrinsic apoptosis by mediating cleavage of RIPK1. Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP. Cleaves phospholipid scramblase proteins XKR4 and XKR9. In addition to apoptosis, involved in different forms of programmed cell death. Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity. PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis. Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death. Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis. Regulates B-cell programs both during early development and after antigen stimulation. (Microbial infection) Proteolytically cleaves the N protein of coronaviruses such as MERS-CoV and SARS-CoV. The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes. The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11) subunits. Interacts with BIRC6/bruce. Interacts with RIPK3. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated by NUAK1; phosphorylation inhibits self-activation. Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis. Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity. Can be cleaved and activated by different caspases, depending on the context. Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain. Cleaved and activated by CASP1, possibly in the context of inflammation.

Activity regulation. During activation, the N-terminal disordered prodomain is removed by cleavage. Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit. The two large and two small subunits then assemble to form the active CASP6 complex. Can be cleaved and activated by different caspases, depending on the context. Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain. Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation. Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation. Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation. Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone).

Domain organisation. The N-terminal disordered prodomain is required to prevent self-activation. The Tri-arginine exosite is required to recruit substrates for hydrolysis. Undergoes helix-strand structural transitions upon substrate-binding: the 130’s region interconverts between an inactive helical state and the canonically active strand state. Other caspases rest constitutively in the strand conformation before and after substrate-binding.

Similarity. Belongs to the peptidase C14A family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55212-1	Alpha	yes
P55212-2	Beta

RefSeq proteins (2): NP_001217, NP_116787 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR002138	Pept_C14_p10	Domain
IPR002398	Pept_C14	Family
IPR011600	Pept_C14_caspase	Domain
IPR015917	Pept_C14A	Domain
IPR016129	Caspase_his_AS	Active_site
IPR029030	Caspase-like_dom_sf	Homologous_superfamily
IPR033139	Caspase_cys_AS	Active_site

Pfam: PF00656

Enzyme classification (BRENDA)

• EC 3.4.22.59 — caspase-6 (BRENDA: 8 organisms, 159 substrates, 141 inhibitors, 28 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AC-VAL-GLU-ILE-ASP-7-AMIDO-4-TRIFLUOROMETHYLCOUM	0.0227–0.315	7
N-ACETYL-VEID-7-AMIDO-4-METHYLCOUMARIN	0.082–0.176	5
N-ACETYL-VAL-GLU-ILE-ASP-7-AMIDO-4-METHYLCOUMARI	0.0134–0.0306	4
(N-ACETYL-VEID)2-RHODAMINE110	0.08	1
ACETYL-DEVD-4-NITROANILIDE	0.18	1
ACETYL-DQMD-4-NITROANILIDE	1.3	1
ACETYL-LEVD-4-NITROANILIDE	0.16	1
ACETYL-VDQQD-4-NITROANILIDE	7	1
ACETYL-VEHD-7-AMIDO-4-METHYLCOUMARIN	0.17	1
ACETYL-VEID-4-NITROANILIDE	0.03	1
ACETYL-VQVD-4-NITROANILIDE	0.58	1
ACETYL-YEVD-4-NITROANILIDE	1.2	1
N-ACETYL-ASP-GLU-VAL-ASP-7-AMIDO-4-METHYLCOUMARI	0.126	1
N-ACETYL-ASP-GLU-VAL-ASP-7-AMIDO-4-TRIFLUOROMETH	0.087	1
N-ACETYL-VAL-GLU-HIS-ASP-7-AMIDO-4-METHYLCOUMARI	0.246	1

UniProt features (62 total): strand 17, mutagenesis site 12, helix 11, turn 4, sequence variant 3, region of interest 3, propeptide 2, chain 2, modified residue 2, lipid moiety-binding region 2, active site 2, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

showing 30 of 37 structures by resolution:

PDB	Title	Method	Resolution (Å)
3OD5	Crystal structure of active caspase-6 bound with Ac-VEID-CHO	X-RAY DIFFRACTION	1.6
3S70	Crystal structure of active caspase-6 bound with Ac-VEID-CHO solved by As-SAD	X-RAY DIFFRACTION	1.62
4N7J	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	1.67
4NBN	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	1.75
4NBL	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	1.76
8EG6	huCaspase-6 in complex with inhibitor 2a	X-RAY DIFFRACTION	1.82
3P4U	Crystal structure of active caspase-6 in complex with Ac-VEID-CHO inhibitor	X-RAY DIFFRACTION	1.9
4NBK	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	1.94
2WDP	Crystal Structure of Ligand Free Human Caspase-6	X-RAY DIFFRACTION	1.95
4N5D	Tailoring Small Molecules for an Allosteric Site on Procaspase-6: Cpd1	X-RAY DIFFRACTION	2.06
4HVA	Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6	X-RAY DIFFRACTION	2.07
4N7M	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	2.12
8EG5	huCaspase-6 in complex with inhibitor 3a	X-RAY DIFFRACTION	2.14
4N6G	Tailoring Small Molecules for an Allosteric Site on Procaspase-6	X-RAY DIFFRACTION	2.14
3V6L	Crystal Structure of caspase-6 inactivation mutation	X-RAY DIFFRACTION	2.2
8F97	Compound 5 bound to procaspase-6	X-RAY DIFFRACTION	2.32
6DEV	Human caspase-6 E35K	X-RAY DIFFRACTION	2.35
3P45	Crystal structure of apo-caspase-6 at physiological pH	X-RAY DIFFRACTION	2.53
8F9A	Compound 11 bound to procaspase-6	X-RAY DIFFRACTION	2.55
4EJF	Allosteric peptides that bind to a caspase zymogen and mediate caspase tetramerization	X-RAY DIFFRACTION	2.65
3QNW	Caspase-6 in complex with Z-VAD-FMK inhibitor	X-RAY DIFFRACTION	2.65
8F78	Compound 1 bound to procaspase-6	X-RAY DIFFRACTION	2.65
8F9B	Compound 19 bound to procaspase-6	X-RAY DIFFRACTION	2.65
8F9D	Compound 21 bound to procaspase-6	X-RAY DIFFRACTION	2.65
3V6M	Inhibition of caspase-6 activity by single mutation outside the active site	X-RAY DIFFRACTION	2.69
4IYR	Crystal structure of full-length caspase-6 zymogen	X-RAY DIFFRACTION	2.7
8F98	Compound 8 bound to procaspase-6	X-RAY DIFFRACTION	2.7
6DEU	Human caspase-6 A109T	X-RAY DIFFRACTION	2.8
8F9C	Compound 20 bound to procaspase-6	X-RAY DIFFRACTION	2.8
4FXO	Zinc-mediated allosteric inhibiton of caspase-6	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55212-F1	85.54	0.67

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoli fibrillar center; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
121
163

Post-translational modifications (4)

Type	Positions
Phosphoserine	257, 79
S-palmitoyl cysteine	264, 277

Mutagenesis-validated functional residues (12)

Position	Phenotype
23	abolished activation due to the presence of the n-terminal disordered prodomain. abolished processing and subsequent activation; when …
42–44	decreased ability to hydrolyze substrates.
121	catalytically inactive active-site mutant.
135	increased stability.
163	catalytically inactive active-site mutant.
179	abolished processing and subsequent activation; when associated with a-23 and a-193.
193	abolished processing and subsequent activation; when associated with a-23 and a-179.
257	abolished phosphorylation, leading to caspase-6 activation.
257	phospho-mimetic mutant; prevents caspase-6 autoactivation.
257	phospho-mimetic mutant; loss of self-activation.
264	reduced palmitoylation, leading to increased cysteine protease activity.
277	reduced palmitoylation, leading to increased cysteine protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-111465	Apoptotic cleavage of cellular proteins	curated
R-HSA-352238	Breakdown of the nuclear lamina	curated
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins	curated
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases	curated
R-HSA-109581	Apoptosis	—
R-HSA-75153	Apoptotic execution phase	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes	—
R-HSA-3700989	Transcriptional Regulation by TP53	—

MSigDB gene sets: 292 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, chr4q25, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, JI_RESPONSE_TO_FSH_UP, GOBP_INFLAMMATORY_RESPONSE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, LANG_MYB_FAMILY_TARGETS, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION

GO Biological Process (14): activation of innate immune response (GO:0002218), proteolysis (GO:0006508), apoptotic process (GO:0006915), protein autoprocessing (GO:0016540), epithelial cell differentiation (GO:0030855), positive regulation of apoptotic process (GO:0043065), regulation of programmed cell death (GO:0043067), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of necroptotic process (GO:0060545), pyroptotic inflammatory response (GO:0070269), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), cellular response to staurosporine (GO:0072734), hepatocyte apoptotic process (GO:0097284), protein maturation (GO:0051604)

GO Molecular Function (7): cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), identical protein binding (GO:0042802), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Apoptotic cleavage of cellular proteins	2
Apoptotic execution phase	1
TP53 Regulates Transcription of Cell Death Genes	1
Programmed Cell Death	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1
Apoptosis	1

GO top-level categories

40 GO namespaces:

Category	Terms
cellular anatomical structure	4
protein metabolic process	2
programmed cell death	2
peptidase activity	2
activation of immune response	1
positive regulation of innate immune response	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein processing	1
cell differentiation	1
epithelium development	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of cellular process	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of necroptotic process	1
positive regulation of programmed necrotic cell death	1
necroptotic process	1
inflammatory response	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	1
cellular response to alkaloid	1
response to staurosporine	1
epithelial cell apoptotic process	1
gene expression	1
endopeptidase activity	1
cysteine-type peptidase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 18 of 26 annotations. The rest are phylogenetic / computational / electronic (IEA).

18 experimentally-supported GO terms:

GO term	NS	Evidence
activation of innate immune response	BP	direct assay
cellular response to staurosporine	BP	mutant phenotype
epithelial cell differentiation	BP	expression pattern
hepatocyte apoptotic process	BP	direct assay
intrinsic apoptotic signaling pathway by p53 class mediator	BP	direct assay
positive regulation of apoptotic process	BP	direct assay
positive regulation of necroptotic process	BP	direct assay
protein autoprocessing	BP	direct assay
proteolysis	BP	direct assay
pyroptotic inflammatory response	BP	direct assay
regulation of programmed cell death	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
fibrillar center	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
cysteine-type endopeptidase activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,164 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP6	TNFRSF21	O75509	793
CASP6	CASP9	P55211	739
CASP6	CYCS	P00001	724
CASP6	CASP8	Q14790	723
CASP6	DFFB	O76075	697
CASP6	APAF1	O14727	689
CASP6	DFFA	O00273	679
CASP6	BCL2	P10415	651
CASP6	APP	P05067	629
CASP6	FADD	Q13158	617
CASP6	BAX	P55269	616
CASP6	GSDME	O60443	602
CASP6	GSDMC	Q9BYG8	592
CASP6	CASP3	P42574	588
CASP6	BCL2L1	Q07817	582

IntAct

Human interaction partners of CASP6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 210 partners by confidence:

Partner	Interaction type	MIscore	Records
CASP3	cleavage reaction	0.570	2
HTT	physical association	0.560	15
ACTL7B	physical association	0.560	3
ADAL	physical association	0.560	3
ADAMTSL4	physical association	0.560	3
AK8	physical association	0.560	3
AKR1C8	physical association	0.560	3
ALKBH3	physical association	0.560	3
AMDHD2	physical association	0.560	3
ANKEF1	physical association	0.560	3
ANXA4	physical association	0.560	3
APOA4	physical association	0.560	3
APOBEC4	physical association	0.560	3
ARL6IP4	physical association	0.560	3
ASCL4	physical association	0.560	3
ATF4	physical association	0.560	3
ATG10	physical association	0.560	3
BAAT	physical association	0.560	3
BCAT1	physical association	0.560	3
BCHE	physical association	0.560	3
BRWD1	physical association	0.560	3
BTBD9	physical association	0.560	3
C11orf54	physical association	0.560	3
C1D	physical association	0.560	3
C3orf36	physical association	0.560	3
C4orf33	physical association	0.560	3
CAPN2	physical association	0.560	3
CAPN3	physical association	0.560	3
CBX4	physical association	0.560	3
CCNC	physical association	0.560	3

BioGRID (53 interactions; top human partners by supporting records): CASP3 (Co-localization; 3 records), CASP8 (Biochemical Activity; 3 records), USP15 (Affinity Capture-MS; 3 records), MAPT (Biochemical Activity; 2 records), SATB1 (Affinity Capture-Western; 2 records), STUB1 (Protein-peptide; 2 records), APP (Co-localization), CASP10 (Biochemical Activity), CHD3 (Two-hybrid), COPS6 (Biochemical Activity), CRYAB (Affinity Capture-Western), CSK (Synthetic Lethality), EPHA4 (Co-fractionation), GBP3 (Affinity Capture-MS), IKBKG (Two-hybrid)

SIGNOR signaling

showing 12 of 16 signaling interactions:

A	Effect	B	Mechanism
CASP6	up-regulates	CASP8	cleavage
“Caspase 8 complex”	up-regulates	CASP6	cleavage
“Caspase 3 complex”	up-regulates	CASP6	cleavage
CASP8	up-regulates	CASP6	cleavage
CASP3	up-regulates	CASP6	cleavage
CASP6	down-regulates	LMNA	cleavage
NUAK1	“down-regulates activity”	CASP6	phosphorylation
CASP6	“form complex”	“Caspase 6 complex”	binding
CASP6	“up-regulates activity”	N	cleavage
CASP6	“up-regulates activity”	PSEN2	cleavage
CASP6	“up-regulates activity”	PSEN1	cleavage
CASP6	“up-regulates activity”	APP	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 210 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of PTEN gene transcription	7	9.8×	4e-03
SUMOylation of chromatin organization proteins	7	8.7×	4e-03
Autophagy	7	8.1×	5e-03
Macroautophagy	8	7.2×	4e-03

Disease & clinical

Genetic variants

Variant evidence for CASP6: 59 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

59 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 528):

Position(s)	Effect	Δscore	Sites
4:109694523–109694524	donor_loss	1.0000	4
4:109694701–109694702	acceptor_loss	1.0000	6
4:109694703	acceptor_gain	1.0000
4:109694713–109694714	acceptor_gain	1.0000	2
4:109689569–109689570	acceptor_loss	0.9900	5
4:109690848–109690849	donor_loss	0.9900	5
4:109691010–109691011	acceptor_loss	0.9900	4
4:109698298–109698299	donor_loss	0.9900	6
4:109698343–109698344	acceptor_loss	0.9900	6
4:109689569	acceptor_loss	0.9800

AlphaMissense

807 missense substitutions predicted likely pathogenic (of 1,943 scored), across 184 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M39	9	0.837	0.971
M281	9	0.778	0.987
D70	8	0.988	0.995
H121	8	0.988	0.997
D205	8	0.987	0.996
F83	8	0.949	0.995
D169	8	0.944	0.982
F158	8	0.940	0.995
D112	8	0.936	0.980
F143	8	0.934	0.994
D231	8	0.893	0.949
F206	8	0.874	0.989
F278	8	0.874	0.989
F50	8	0.863	0.991
D193	8	0.831	0.925
F114	8	0.807	0.982
W227	7	0.992	0.997
R64	7	0.983	0.998
F55	7	0.977	0.997
C163	7	0.963	0.992

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (TCGA)	favorable	0.00048

Disease associations

OMIM: gene MIM:601532 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST007323_92	Risk-taking tendency (4-domain principal component model)	2e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3308 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 176,273 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

10 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1200885	ALOSETRON HYDROCHLORIDE	4	3,213
CHEMBL459	METHYLDOPA	4	22,131
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	114,909
CHEMBL1200843	METHYLERGONOVINE MALEATE	4	1,151
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1454910	NITROXOLINE	4	1,882
CHEMBL43128	PRIMAQUINE PHOSPHATE	4	2,039
CHEMBL464982	GAMOLENIC ACID	3	26,834
CHEMBL508338	THIMEROSAL	3
CHEMBL98123	PAPAVERINE HYDROCHLORIDE	2	4,110

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
Ac-VEID-CHO	Inhibition	8.1	pIC50

Binding affinities (BindingDB)

179 measured of 290 human assays (293 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
[3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-carboxy-2-oxo-butyl]-hexyl-methyl-ammonium; chloride	IC50	0.05 nM
[3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-carboxy-2-oxo-butyl]-methyl-pentyl-ammonium; chloride	IC50	0.11 nM
(3S)-3-[(2S)-6-(6-{5-[(3aS,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanamido}hexanamido)-2-[(2S)-2-{[(benzyloxy)carbonyl]amino}-4-carboxybutanamido]hexanamido]-5-[(2,6-dimethylphenyl)carbonyloxy]-4-oxopentanoic acid	KI	6.3 nM
(4S,7S,10S,13S)-10-sec-butyl-7-(2-carboxyethyl)-13-formyl-4-isopropyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecan-15-oic acid	IC50	8 nM
2-(2-((S)-2-(benzyloxycarbonyl)-3-methylbutanamido)benzamido)-4-fluoro-3-oxobutanoic acid	IC50	12 nM
CHEMBL5563896	IC50	12 nM
N-(2-Hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-[2-(naphthalen-1-ylamino)-acetylamino]-butyramide	IC50	15 nM
CHEMBL1091826	EC50	16 nM
CHEMBL2323966	IC50	20 nM
CHEMBL2324340	IC50	26 nM
4-Methyl-2-[2-(naphthalen-1-ylamino)-acetylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	33 nM
{1-[1-(2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-3-methyl-butylcarbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester	IC50	43 nM
4-(2-Acetylamino-3-carboxy-propionylamino)-4-[1-((S)-2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-methyl-propylcarbamoyl]-butyric acid	IC50	50 nM
4-(2-Acetylamino-2-carboxy-acetylamino)-4-[1-(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-methyl-propylcarbamoyl]-butyric acid	IC50	50 nM
(4S)-4-{[(1S)-1-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}-2-methylbutyl]carbamoyl}-4-[(2S)-2-acetamido-3-methylbutanamido]butanoic acid	IC50	60.5 nM
CHEMBL5419962	KD	80 nM
4-Methyl-2-[2-(naphthalen-1-ylamino)-propionylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	87 nM
N-(2-Hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-[2-(5-trifluoromethanesulfonylamino-naphthalen-1-yloxy)-acetylamino]-butyramide	IC50	127 nM
2-[2-(2,4-Dichloro-naphthalen-1-yloxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	141 nM
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
CHEMBL4211859	IC50	160 nM
CHEMBL5440664	KD	180 nM
CHEMBL5399818	KD	220 nM
4-oxo-4-(piperidin-1-yl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide	IC50	231 nM
2-oxo-1-phenyl-2-[(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]ethyl acetate	IC50	233 nM
N-(2-Hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-[3-(naphthalen-1-yloxy)-propionylamino]-butyramide	IC50	250 nM
CHEMBL5422136	KD	310 nM
4-Methyl-2-[2-(3-phenoxy-phenylamino)-acetylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	330 nM
N-(2-Hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-[2-(naphthalen-1-yloxy)-acetylamino]-butyramide	IC50	336 nM
1-{[1-(2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-propylcarbamoyl]-methoxy}-naphthalene-2-carboxylic acid	IC50	385 nM
4-Methyl-2-(3-naphthalen-1-yl-3-oxo-propionylamino)-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	408 nM
2-[2-(4-Chloro-naphthalen-1-yloxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	429 nM
CHEMBL3613794	IC50	430 nM
CHEMBL5395946	KD	470 nM
2-[2-(2-Benzyl-phenoxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	521 nM
3-Chloro-N-(1,2,3,4-tetrahydro-1,3,4-trioxoisoquinolin-6-yl)-propanamide	IC50	530 nM
N-(2-Methoxy-phenyl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamide	IC50	537 nM
2-[2-(2-Cyclopentyl-phenoxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	538 nM
4-Methyl-2-(3-naphthalen-2-yl-3-oxo-propionylamino)-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	543 nM
4-Methyl-2-[3-(naphthalen-1-ylsulfanyl)-propionylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	563 nM
4-Methyl-2-[2-(naphthalen-1-yloxy)-acetylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	570 nM
4-Methyl-2-[3-(naphthalen-2-ylsulfanyl)-propionylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	611 nM
2-[2-(Biphenyl-2-yloxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	636 nM
(S)-4-Methyl-2-(3-phenyl-acryloylamino)-pentanoic acid ((S)-2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	650 nM
4-Methyl-2-[3-(naphthalen-1-yloxy)-propionylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	686 nM
CHEMBL5431147	KD	760 nM
2-[2-(2,3-Diphenyl-propylamino)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	790 nM
4-Methyl-2-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	792 nM
2-[2-(4-Methoxy-naphthalen-1-yloxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	831 nM
CHEMBL5417769	IC50	840 nM

ChEMBL bioactivities

459 potent at pChembl≥5 of 726 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	IC50	3.5	nM	CHEMBL101545
8.22	Ki	6	nM	CHEMBL3977587
8.20	Ki	6.3	nM	CHEMBL3917557
8.15	Ki	7	nM	CHEMBL382967
8.14	Ki	7.3	nM	CHEMBL3960740
8.13	Ki	7.4	nM	CHEMBL3927125
8.10	Ki	8	nM	CHEMBL315868
8.10	IC50	8	nM	CHEMBL478081
8.05	Ki	9	nM	CHEMBL91423
8.05	Ki	9	nM	CHEMBL371926
8.05	Ki	9	nM	CHEMBL3983217
8.05	IC50	8.9	nM	CHEMBL5715932
8.00	Ki	10	nM	CHEMBL3944828
8.00	IC50	10	nM	CHEMBL430648
8.00	IC50	10	nM	CHEMBL328412
7.96	Ki	11	nM	CHEMBL88795
7.96	Ki	11	nM	CHEMBL91281
7.96	Ki	11	nM	CHEMBL262735
7.96	Ki	11	nM	CHEMBL3961549
7.96	Ki	11	nM	CHEMBL3926784
7.96	Ki	11	nM	CHEMBL194207
7.92	Ki	12	nM	CHEMBL90185
7.92	IC50	12.12	nM	CHEMBL5563896
7.89	Ki	13	nM	CHEMBL197674
7.89	Ki	13	nM	CHEMBL330534
7.82	Ki	15	nM	CHEMBL199253
7.82	Ki	15	nM	CHEMBL372185
7.82	IC50	15	nM	CHEMBL100643
7.80	Ki	16	nM	CHEMBL88540
7.80	Ki	16	nM	CHEMBL3966591
7.80	EC50	16	nM	CHEMBL1091826
7.79	IC50	16.2	nM	CHEMBL5715932
7.77	Ki	17	nM	CHEMBL3934331
7.77	Ki	17	nM	CHEMBL1199647
7.75	AC50	18	nM	CHEMBL1563898
7.75	IC50	18	nM	CHEMBL23226
7.72	Ki	19	nM	CHEMBL3930460
7.72	Ki	19	nM	CHEMBL3909635
7.72	Ki	19	nM	CHEMBL3910303
7.72	Ki	19	nM	CHEMBL327821
7.70	Ki	20	nM	CHEMBL90268
7.70	Ki	20	nM	CHEMBL3928643
7.70	Ki	20	nM	CHEMBL314096
7.66	Ki	22	nM	CHEMBL3968852
7.66	Ki	22	nM	CHEMBL440211
7.66	Ki	22	nM	CHEMBL3950285
7.64	Ki	23	nM	CHEMBL3907290
7.60	Ki	25	nM	CHEMBL90914
7.60	Ki	25	nM	CHEMBL196266
7.60	Ki	25	nM	CHEMBL3914770

PubChem BioAssay actives

189 with measured affinity, of 742 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49556: Inhibition of Caspase-6	ic50	0.0035	uM
(4S)-4-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-[[(2S,3S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	415378: Inhibition of human recombinant caspase 6 assessed as accumulation of fluorogenic product by fluorometric assay	ic50	0.0080	uM
(4S)-4-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.0080	uM
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49558: Inhibitory concentration of compound required against Caspase-6 enzyme compared to acylated dipeptides	ic50	0.0100	uM
(4S)-4-[[(2R)-2-acetamido-2-carboxyacetyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49557: Inhibitory concentration of compound required against Caspase-6 compared to acylated dipeptides	ic50	0.0100	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[(2-aminoacetyl)amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S,3R)-1-[[(2S)-1-[[(1S)-3-amino-1-carboxy-3-oxopropyl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	2098555: Inhibition of Caspase-6 activity (unknown origin) by FRET assay	ic50	0.0121	uM
(4R)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49556: Inhibition of Caspase-6	ic50	0.0150	uM
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid	49547: Compound was evaluated for its inhibitory activity against the Caspase-6 enzyme	ic50	0.0180	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.0370	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49546: Binding affinity towards human Caspase-6	ic50	0.0370	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylcarbamoyloxy)butanoyl]amino]-4-oxopentanoic acid	240590: Inhibitory concentration against Caspase-6	ic50	0.0500	uM
4-fluoro-2-[[2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]benzoyl]amino]-3-oxobutanoic acid	302015: Inhibition of human caspase 6	ic50	0.0610	uM
5-fluoro-2-[[[3-(1,2,4-triazin-3-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.0800	uM
5-[[5-[[(2S)-1-carboxy-4-(2-chlorophenyl)sulfanyl-3-oxobutan-2-yl]carbamoyl]-2-pyridinyl]methylsulfamoyl]-2-hydroxybenzoic acid	49549: Inhibitory activity against Caspase-6	ki	0.1200	uM
5-[[5-[[(2S)-1-carboxy-4-[(2-chlorophenyl)methylsulfanyl]-3-oxobutan-2-yl]carbamoyl]-2-pyridinyl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.1200	uM
4-oxo-4-piperidin-1-yl-N-(1,3,4-trioxoisoquinolin-6-yl)butanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.1240	uM
N’-(2-methoxyphenyl)-N-(1,3,4-trioxoisoquinolin-6-yl)butanediamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.1370	uM
2-(1-benzyl-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1510	uM
2-[5-(azetidin-1-ylsulfonyl)-1-benzyl-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1560	uM
5-fluoro-2-[[(3-pyrazin-2-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.1800	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1880	uM
5-[[5-[[(2S)-1-carboxy-4-[(2-chlorophenyl)methylsulfanyl]-3-oxobutan-2-yl]carbamoyl]pyrimidin-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.1900	uM
2-[5-(azetidin-1-ylsulfonyl)-1-[(4-methoxyphenyl)methyl]-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1970	uM
4-oxo-4-[(1,3,4-trioxoisoquinolin-6-yl)amino]butanoic acid	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2010	uM
[2-oxo-1-phenyl-2-[(1,3,4-trioxoisoquinolin-5-yl)amino]ethyl] acetate	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2160	uM
5-fluoro-2-[[[3-(1H-1,2,4-triazol-5-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.2200	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2300	uM
2-(1-benzyl-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2410	uM
5-fluoro-2-[[(3-pyrimidin-2-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.2700	uM
2-[5-(azetidin-1-ylsulfonyl)-1-[(3,4-dichlorophenyl)methyl]-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2800	uM
3-chloro-N-(1,3,4-trioxoisoquinolin-6-yl)propanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2830	uM
(2S)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-(3-naphthalen-1-yloxypropanoylamino)pentanamide	49555: Inhibitory concentration required against caspase-6	ic50	0.3050	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[[2-(3-phenoxyanilino)acetyl]amino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.3080	uM
5-fluoro-2-[[[3-(1-methyltriazol-4-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.3100	uM
(2S)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[2-(naphthalen-1-ylamino)propanoylamino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.3100	uM
2-(1-benzyl-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.3250	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.3580	uM
2-[2-oxo-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1H-indol-3-ylidene]propanedinitrile	292077: Inhibition of human recombinant caspase 6	ic50	0.4070	uM
2-(1-benzyl-5-morpholin-4-ylsulfonyl-2-oxoindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4250	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	591189: Inhibition of caspase 6 by fluorometric assay	ic50	0.4500	uM
2-[1-[(4-methoxyphenyl)methyl]-5-morpholin-4-ylsulfonyl-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4530	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4680	uM
5-fluoro-2-[[(3-pyridazin-3-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.4700	uM
isoquinoline-1,3,4-trione	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.4740	uM
2-[1-[[4-(2-fluoroethoxy)phenyl]methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	591189: Inhibition of caspase 6 by fluorometric assay	ic50	0.5090	uM
2-[1-[(4-bromophenyl)methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	292077: Inhibition of human recombinant caspase 6	ic50	0.5150	uM
5-[[5-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]thiophen-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.5400	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.5450	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.5680	uM

CTD chemical–gene interactions

141 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects reaction, increases activity, increases cleavage, increases reaction, affects cotreatment (+1 more)	4
Doxorubicin	affects activity, increases activity, increases expression, affects reaction	4
Estradiol	decreases activity, increases degradation, decreases reaction, affects expression, decreases expression	4
pyrazolanthrone	decreases reaction, increases cleavage, increases activity	3
Arsenic	increases expression, affects cotreatment, decreases expression	3
Mustard Gas	increases activity, increases cleavage, increases reaction, affects reaction	3
Quercetin	decreases expression, increases activity, increases expression	3
Tretinoin	affects cotreatment, decreases expression	3
Valproic Acid	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Bortezomib	increases cleavage, increases reaction	2
Acetylcysteine	decreases reaction, increases cleavage, increases activity	2
Air Pollutants	decreases expression, increases abundance	2
Aspirin	decreases reaction, increases activity, increases cleavage	2
Benzo(a)pyrene	affects methylation, increases expression	2
Cannabidiol	decreases expression, affects cotreatment	2
Deoxycholic Acid	decreases reaction, increases activity, affects response to substance	2
Drugs, Chinese Herbal	decreases expression, increases activity	2
Fluorouracil	affects expression, increases activity, increases cleavage, affects reaction	2
Hydrogen Peroxide	affects expression	2
Indomethacin	affects cotreatment, increases expression, affects reaction, increases activity, decreases reaction (+1 more)	2
Plant Extracts	affects cotreatment, increases expression, increases activity	2
Tobacco Smoke Pollution	increases expression	2
Cladribine	increases activity, increases reaction	2
Particulate Matter	increases abundance, decreases expression	2
7-hydroxydehydronuciferine	increases cleavage	1
moringin	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
intybin	decreases expression	1

ChEMBL screening assays

86 unique, capped per target: 81 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006644	Binding	Inhibition of human recombinant caspase 6 assessed as accumulation of cleaved fluorogenic 7-amino-4-methylcoumarin after 10 mins	Fluorinated isatin derivatives. Part 2. New N-substituted 5-pyrrolidinylsulfonyl isatins as potential tools for molecular imaging of caspases in apoptosis. — *J Med Chem*
CHEMBL5723100	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002178aAD CASP6	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1VI	Abcam A-549 CASP6 KO	Cancer cell line	Male
CVCL_D2A4	Abcam HCT 116 CASP6 KO	Cancer cell line	Male
CVCL_D6AH	HyCyte A-549 KO-hCASP6	Cancer cell line	Male
CVCL_D9ZF	Ubigene HeLa CASP6 KO	Cancer cell line	Female
CVCL_F5GS	EDITGENE CASP6 Knockout HAP1 Cell Line	Cancer cell line	Male
CVCL_SG94	HAP1 CASP6 (-) 1	Cancer cell line	Male
CVCL_SG95	HAP1 CASP6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CASP6 across ~30M SureChEMBL compounds — explore on Sugi Predict.